Dasatinib monohydrate of Formula A, chemically, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide monohydrate, is a cyclic protein tyrosine kinase inhibitor. Dasatinib monohydrate is marketed under the brand name SPRYCEL® and is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior therapy including imatinib. SPRYCEL® is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

The compound of Formula 1a,
wherein R1 and R2 can be independently selected from the group consisting of hydrogen, amino protecting group, and 6-chloro-2-methyl-pyrimidin-4-yl, 6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl, encompasses dasatinib of Formula B,
and key intermediates of dasatinib of Formula 1b, Formula 1c, and Formula 1d, or salts thereof

U.S. Pat. No. 6,596,746 provides a process for the preparation of tert-butyl {5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}carbamate (Formula 1b), 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c), and N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d) which are the intermediates for the preparation of dasatinib.
The process provided in the '746 patent for the preparation of tert-butyl {5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}carbamate (Formula 1b), 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c), and N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d) involves four, five, and six synthetic steps, respectively, starting from ethyl 2-amino-1,3-thiazole-5-carboxylate as depicted in the chemical scheme below:

The first step of the process involves stirring a suspension of ethyl 2-amino-1,3-thiazole-5-carboxylate, 4-dimethylaminopyridine, and di-tert-butyl dicarbonate in dry tetrahydrofuran for a time period of 24 hours. The solvent was evaporated in vacuo and the residue obtained was suspended in ether, washed with ether, and dried in vacuo to obtain ethyl 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate.
The second step involves treating a stirred solution of ethyl 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate in tetrahydrofuran-methanol with 6N aqueous sodium hydroxide solution at room temperature for 24 hours. Most of the tetrahydrofuran-methanol were removed by distillation under reduced pressure and the aqueous solution was acidified with 6N hydrochloric acid to obtain a solid which was filtered, washed with water and ether, then air dried, followed by drying in vacuo to obtain 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid.
The third step involves adding a 2M solution of oxalyl chloride in dichloromethane to a stirred solution of 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid in tetrahydrofuran and N,N-dimethylformamide, and then stirring the solution at room temperature for 4 hours. The solvent was evaporated under reduced pressure and in vacuo to obtain tert-butyl[5-(chlorocarbonyl)-1,3-thiazol-2-yl]carbamate.
The fourth step involves adding 2-chloro-6-methylaniline to a stirred solution of tert-butyl[5-(chlorocarbonyl)-1,3-thiazol-2-yl]carbamate in dichloromethane at 0° C. Diisopropylamine was added to the reaction mixture, warmed to room temperature, stirred for 24 hours, diluted with dichloromethane, and washed with 2N hydrochloric acid. The organic extract thus obtained was dried, filtered, and concentrated to obtain a residue. The residue was diluted with ethyl acetate-ether, filtered, washed with ether, and dried in vacuo to obtain tert-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}carbamate (Formula 1b) in an overall yield of 48%.
The fifth step involves treating tert-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}carbamate (Formula 1b) obtained in the fourth step with trifluoroacetic acid at room temperature to obtain 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c).
The sixth step involves reacting 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c) with 4,6-dichloro-2-methylpyrimidine in the presence of sodium hydride in tetrahydrofuran to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d).
The seventh step of the process involves reacting N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d) obtained in the sixth step with 1-(2-hydroxyethyl)piperazine to obtain dasatinib of Formula B.
J. Med. Chem., 47(27), 6658-6661 (2004), provides a four step process for the preparation of N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d) from 2-chlorothiazole.
The first step of the process involves reacting 2-chlorothiazole with 2-chloro-6-methylphenylisocyanate in the presence of n-butyl lithium in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide. The second step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide with 4-methoxybenzylchloride in the presence of sodium hydride in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The third step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with 4-amino-6-chloro-2-methylpyrimidine in the presence of sodium hydride in tetrahydrofuran at reflux temperature to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The fourth step involves reacting N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with trifluoromethanesulfonic acid and trifluoroacetic acid in dichloromethane to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d).
PCT Publication No. WO 2005/077945 provides a process for the preparation of 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c) which involves adding 3-ethoxyacryloyl chloride to a cold stirring solution of 2-chloro-6-methylaniline and pyridine in tetrahydrofuran at a temperature of 0° C. to 5° C. The mixture thus obtained was then warmed, stirred for 2 hours at 20° C., and hydrochloric acid was added at 0° C. to 10° C. The mixture was diluted with water and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene and stirred for 15 minutes at 20° C. to 22° C. then for 1 hour at 0° C. to obtain (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide.
N-Bromosuccinamide was added to a mixture of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide in 1,4-dioxane and water at −10° C. to 0° C. to obtain a slurry which was warmed and stirred at 20° C. to 22° C. for 3 hours. Thiourea was added and the mixture was heated to 80° C. After 2 hours, the resulting solution was cooled to 20° C. to 22° C. and concentrated ammonium hydroxide was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0° C. to 5° C. to obtain a solid which was collected by vacuum filtration, washed with cold water, and dried to obtain 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Formula 1c).
Several processes are known in the literature for the preparation of 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c), for example, PCT Publication Nos. WO 2007/019210, WO 2007/106879, WO 2008/076883, and WO 2010/144338.
Several processes are known in the literature for the preparation of N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d), for example, U.S. Publication No. US 2006/0004067; PCT Publication Nos. WO 2007/106879 and WO 2011/095125; ARKIVOC, 2010(6), 32-38 (2010); and J. Med. Chem., 49(23), 6819-6832 (2006).
The processes described in the prior art for the preparation of tert-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}carbamate (Formula 1b), 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c), and N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d) suffer from one or more disadvantages such as a low yield, high number of chemical reaction steps, difficulties in isolation of the products, and usage of hazardous reagents such as oxalyl chloride, thionyl chloride, n-butyl lithium, and N-bromosuccinamide. Therefore, processes described in the prior art for the preparation of tert-butyl {5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}carbamate (Formula 1b), 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c), and N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d) are believed to be unsuitable and/or undesirable for commercial scale production.